GIT Hormones
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Transcript of GIT Hormones
MUHAMMAD RAMZAN UL REHMAN 1
GI GI hormonhormonee
BY MUHAMMAD RAMZAN UL REHMAN
MUHAMMAD RAMZAN UL REHMAN 2
Regulation of GI function Endocrine regulation : EEC secretes regulatory peptide or hormones that travel via blood stream to remote target organ. ◦ Ex gastrin, secretin
Paracrine regulation : regulatory peptide secreted by EEC acts on a nearby target cell by diffusion through interstitial space.◦ Ex histamine
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Regulation of GI function Autocrine : regulatory peptide secreted by the cells acting on themselves.
Juxtacrine : 1 regulatory peptide acts on many target cells.
Neurocrine : through nerves and neurotransmitters.
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Hormone/peptide neurocrine endocrine paracrine
VIP +Substance P +Neuropeptide +Somotostatin + + +Cholecystokinin + +Gastrin +Secretin +GIP +Motilin + +Neurotensin ? + +Guanylin + +
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Enteroendocrine cell (EEC)Hormone-secreting cells in the mucosa of stomach, small intestine, colon
produce by : G cell, S cell
Produce 5-HT & hormones : enterochromaffin cell
Produce amine or polypeptide : neuroendocrine cell (APUD: Amine Precursor Uptake and Decarboxylase)
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Enteroendocrine cell (EEC) Have 2 types
Open-type : apical membrane contact with GI lumen (receptor), secretion occurs in basolateral membrane ex. G cell
Closed-type : No contact with luminal surface ex. Enterochromaffin-like cell (ECL) which secretes histamine
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GI hormones Classified by similarity in structure and function
1. Gastrin family : gastrin, CCK
2. Secretin family : secretin, glucagon, glicentin, VIP, GIP
3. Others (not fit in either family) : motilin, substance P, GRP, guanylin
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Gastrin Produced by G cell in the mucosal gland of gastric antrum and duodenum
Can be found in fetal pancreatic islet, hypothalamus, medulla oblongata, vagus n. (unidentified function)
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Structure of gastrin Polypeptide hormone with multiple forms
1. Macroheterogenity : diff in length of peptide chain
2. Microheterogenity : diff on derivatization of amino acid residues
ex. Sulfation of tyrosine (6th aa residue from C-terminal), amidation of the C-terminal phynylalanine
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Structure of gastrin Preprogastrin (101 aa) is processed into 3 fragments
1. G34 : 34 aa secreted mainly by duodenal G cell
2. G17 : 17 aa secreted mainly by antral G cell
3. G14 : 14 aa
All forms have the same C-terminal configuration
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Structure of gastrin
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Gastrin Different forms, different activity, different tissues that are found
G17 : principal form of gastric acid secretion (more active and more amount than G34)
Half Life (t1/2) : G14, G17 2-3 min in blood.
G34 15 min Inactivated in kidney, small bowel
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Action of gastrin Stimulation of gastric acid and pepsin secretion
Stimulation of mucosal growth in stomach, SB, colon (trophic action)
Stimulation of gastric motility
Release of histamine from ECL cell
Stimulate insulin secretion after protein meal (not CHO)
+/- constriction of LES
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Regulation of gastrin secretion ↑ gastrin secretion
Luminal : peptide, aa (Phy, Tryp), gastric distention
Neural : vagal stimulation via GRP (can’t be blocked by atropine)
Blood : Ca, epinephrine
↓ gastrin secretion
Luminal : acid, somatostatin
Blood : secretin, GIP, VIP, glucagon, calcitonin
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Feedback inhibition of gastrin Acid in antrum inhibit gastrin secretion by 2 ways
1. Direct action on G cell
2. Stimulate release of somatostatin by D cell
In condition which parietal cells are damaged, pernicious anemia, gastrin level is elevated.
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Cholecystokinin-Pancreozymin (CCK)
Also shows macro- and microheterogenity Prepro-CCK is processed into several fragments
CCK58, CCK39, CCK33, CCK22 ,CCK12, CCK8
Every forms has the same 5 aa at C-terminal as gastrin
Every forms has amidation of C-terminal, sulfation of 7thtyrosine from C-terminal
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CCK Secreted by I cell in duodenum and jejunum
Also found in nerves in distal ileum and colon, neurons in brain (regulation of food intake)
CCK8, CCK22, CCK33 : principal circulating forms secreted in response to meal
Enteric & pancreatic nerve : CCK4
Brain : CCK8, CCK58
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Action of CCK Gall bladder contraction, sphincter of Oddi relaxation
↑ pancreatic enzyme secretion
Augment effect of secretin in producing alkaline pancreatic juice
↓ gastric emptying
Trophic effect on pancrease
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Action of CCK ↑ secretion of enterokinase
↑ motility of small intestine and colon
Augment contraction of pyloric sphincter (↓ duodenal reflux)
↑ glucagon secretion (work with gastrin)
Induced satiety by acting through hypothalamus
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Mechanism of action Through CCK receptor (2 type)
1. CCK-A : locates in periphery, brain
2. CCK-B : locates in brain
CCK bind to receptor activate phospholipase C → IP3, DAG → ↑ intracellular Ca → activate protein kinase → release of granule (pancreatic enzyme)
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Mechanism of action CCK also stimulate vagus nerve to pancrease (via CCK-A receptor) → release of Ach, GRP, VIP → fusion of granule with membrane and release of pancreatic enzyme
Gastrin receptor is very similar to CCK-B receptor.
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Mechanism of action
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Control of CCK secretion Most potent stimulator of CCK release is lipid
Peptones, amino acid also increase CCK release but CHO has little effect.
Also secreted in response to CCK-releasing factor
Positive feedback : CCK → enzyme release → more digestive products → more CCK (stop when digestive products move to next part)
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CCK-releasing peptide & monitor peptide
CCK-RP is secreted from duodenal mucosa, and monitor peptide by pancreatic acinar cell
Secreted in response to fat, protein digestive products, and also to neural input (cephalic phase)
Match the release of CCK, pancreatic enzyme and the need for enzyme to digest foods
These peptides are degraded by pancreatic trypsin (if there are proteins in duodenum, these peptides won’t be degraded and CCK will be released )
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Secretin 27 amino-acid polypeptide
Secreted by S cell located deeply in the mucosal gland of duodenum and jejunum
Similar structure with glucagon, VIP, GIP
Only 1 form has been isolated
t1/2 : 5 min
Stored in an inactive form (prosecretin)
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Action of secretin Most potent humoral stimulator of fluid and HCO3 secretion by pancrease
Acts in concert with CCK, Ach to stimulate HCO3 secretion
↑ HCO3 secretion by duct cells of pancrease and biliary tract→ ↑secretion of a watery, alkaline pancreatic juice
Acting through cAMP
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Action of secretin ↑ pancreatic enzyme secretion (augment CCK) ↓ gastric acid secretion Pyloric sphincter contraction Stimulate growth of exocrine pancrease (work with CCK)
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Mechanism of action
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Effect of secretin on bile secretion
Produce a watery bile rich in HCO3
Activate via cAMP → stimulate CFTR (Chloride channel) and Cl– HCO3 exchanger
Work in concert with glucagon, VIP
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Action of secretin in bile secretion
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Control of secretin secretion Secretin is secreted in response to protein digestive products, bile acid, fatty food and increased acidity in duodenal content (pH< 4.5-5) Inhibited by somatostatin and Met-enkephalin Secretin release may be mediated by secretin-releasing peptide
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Gastric inhibitory peptide (GIP) 42 amino-acid polypeptide
Produced by K cell in duodenal and jejunal mucosa
Stimulated by glucose and fat in duodenum, acid in stomach
Inactivated by dipeptidyl-peptidase IV (DPP-IV)
in many tissues and in portal circulation
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Action of GIP Mild effect in decreasing gastric motility
Inhibit gastric acid secretion by directly inhibit parietal cells or indirectly inhibit gastrin release from antral G cells (via somatostatin)
Stimulate insulin release from pancreatic islet in response to duodenal glucose and fatty acid
Oral glucose can stimulate larger amount of insulin release than IV glucose
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Enteric factors increasing insulin release
CCK, GIP, GLP-1, Glucagon
GIP is also called glucose-dependent insulinotropic polypeptide by this action
GLP-1 is more potent than GIP (limited study)
GIP, GLP-1 act via protein kinase A pathway (increased cAMP and cytosolic calcium)
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Glucagon-Like Peptide 1 (GLP-1) 30 amino-acid polypeptide
Incretin hormone : intestinal hormone secreted in response to nutrient ingestion which potentiate glucose-induced insulin release
Produced by L cell in ileum and colon, pancreatic alpha cell, neurons in hypothalamus, pituitary gland
2 bioactive forms : GLP-1[7-36] amide , GLP-1[7-37] both forms are equipotent, same t1/2
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GLP-1 Derivative of glucagon
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Glucagon Produced by alpha cell of pancreatic islet
Action :
Increase glycogenolysis
Increase gluconeogenesis
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hyperglycemia
Glicentin 69 amino-acid polypeptide derived from proglucagon
Secreted from L cell along with GLP-1 and GLP-2
Action : stimulation of insulin secretion, inhibit gastric acid secretion, regulation of gut motility, stimulation of intestinal growth
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Vasoactive intestinal peptide (VIP)
28 amino-acid polypeptide
Found in ENS neurons (both myenteric and submucosal plexus), brain, autonomic nerves
Released in response to esophageal and gastric distention, vagal stimulation, fatty acid and ethanol in duodenum
Amino acid and glucose don’t affect VIP release
Half life 2 min in circulation
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Action of VIP ↑ secretion of E’lyte and water from small bowel
Intestinal circular smooth ms relaxation
Longitudinal smooth muscle contraction
↑ pancreatic secretion
Inhibit gastric acid secretion and motility
Potentiate axn of Ach in salivary gland
VIPoma : presented with profused diarrhea
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Motilin 22 amino-acid polypeptide
Secreted by enterochromaffin cell and M cell in duodenum, jejunum
Acts on G-protein coupled receptor on enteric neurons in stomach, duodenum → GI tract smooth muscle contraction
Its circulating level increased at interval of 90-100 mins in the interdigestive state
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Motilin Major regulator of MMCs (Migrating Motor Complex) that move through the stomach and small intestine every 90 mins in fasted person
Motilin secretion is inhibited after ingestion
Vagal nerve may play some role in motilin secretion
Erythromycin bind to motilin receptor → ↑ GI motility in constipated person
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Somatostatin Growth hormone inhibitory hormone (GH-IH)
First found in hypothalamus
Secreted by D cell in stomach, duodenum, pancreatic islet
Secreted in larger amount into gastric lumen > circulation
Released in response to acid in stomach
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somatostatin Presented in 2 forms
1. Somatostatin 14 : prominent in hypothalamus
2. Somatostatin 28 : prominent in GI tract
Acts through G-protein couple receptor (inhibit adenylate cyclase)
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Action of somatostatin Inhibit secretion of gastrin, VIP, GIP, secretin, motilin, GH, insulin, glucagon
↑ fluid absorption and ↓ secretion from intestine
↓ endocrine and exocrine pancreatic secretion
↓ bile flow and gall bladder contraction
↓ gastric acid secretion and motility
↓ absorption of glucose, amino acid, triglyceride
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Summation of GI hormone
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Hormone Source Target ActionCholecystokinin
I cell in duo, jeju, neurons in ileum, colon
Pancrease
gallbladder
↑enz secretion
↑contraction
GIP K cell in duo, jeuju
pancrease ↓fluid absorp
↑insulin release
Gastrin G cell in antrum, duo
Parietal cell ↑acid secretion
↑motility
GRP Vagus nerve G cell Gastrin release
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Hormone Source Target ActionGlucagon Alpha cell in
pancreatic islet
liver ↑glycogenolysis
↑gluconeogenesis
Guanylin Ileum, colon Small and large intestine
↑fluid secretion
Motilin EC cell, Mo cell in upper GI tract
Eso sphincter
Stomach, duo
Smooth muscle contraction
Neurotensin Neurons, ECC in ileum
Intestinal smooth muscle
↓ GI motility
↑ blood flow
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Hormone Source Target ActionPeptide YY L cell in
ileum, colonStomach
Pancrease
↓ vagal mediated acid secretion
↓ enz and fluid secretion
Secretin S cell in small intestine
Pancrease
Stomach
↑HCO3 and fluid secretion by pancreatic ducts
↓ gastric a secretion
somatostatin D cell in stomach , duodenum, pancreatic islet
Stomach
Intestine
Pancrease
Liver
↓ gastrin release
↑fluid absorption
↑smm contraction
↓endo/exocrine secretion
↓bile flow
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Hormone Source Target Action
Substance P Enteric neurons
Intestine
Pancrease
↑GI motility
↓HCO3 secretion
VIP ENS neurons Small intestine
Pancrease
smm contraction
↑SB secretion
↑pancreatic secretion
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Thank You BY MUHAMMAD RAMZAN UL REHMAN
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